Metastatic colorectal cancer: current state and future directions.

Published Ahead of Print on April 27, 2015 as 10.1200/JCO.2014.59.7633 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2014.59.7633

JOURNAL OF CLINICAL ONCOLOGY

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Metastatic Colorectal Cancer: Current State and Future Directions Marwan G. Fakih Marwan G. Fakih, Gastrointestinal Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA.

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Corresponding author: Marwan G. Fakih, MD, City of Hope, 1500 E Duarte Rd, Building 51, Room 127, Duarte, CA 91010; e-mail: [email protected].

Substantial improvements have been made in the management of metastatic colorectal cancer over the last two decades. The overall survival of patients diagnosed with unresectable metastatic colorectal cancer has increased from approximately 1 year during the era of fluoropyrimidine monotherapy to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. More effective therapeutic combinations have increased the rate of curative-intent surgical resections, resulting in median survival in this subgroup that exceed 5 years. Here we review the landscape of systemic therapies for unresectable metastatic colorectal cancer during the current era of targeted therapies, review the effects of RAS and BRAF mutations on clinical decision making, and reflect on future directions for the treatment of metastatic colorectal cancer.

© 2015 by American Society of Clinical Oncology

J Clin Oncol 33. © 2015 by American Society of Clinical Oncology

Published online ahead of print at www.jco.org on April 27, 2015. Author’s disclosures of potential conflicts of interest are found in the article online at www.jco.org.

0732-183X/15/3399-1/$20.00 DOI: 10.1200/JCO.2014.59.7633

INTRODUCTION

Colorectal cancer (CRC) continues to be the second leading cause of cancer-related death in the United States. It is projected that 136,830 individuals will be diagnosed with CRC in 2014 in the United States, 50,310 of whom will succumb to this disease.1 The current approach to treating metastatic CRC (mCRC) favors the use of combination cytotoxic therapy. First-line treatments include the doublet cytotoxic combinations of fluorouracil, leucovorin, and irinotecan (FOLFIRI), infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX), and capecitabine plus oxaliplatin (XELOX), as well as the triplet combination fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI).2-5 The US Food and Drug Administration approval of several angiogenesis-targeting and epidermal growth factor receptor (EGFR) –targeting agents has improved clinical outcomes and has added further complexity to treatment decisions. Here, we limit our review to the current landscape of targeted therapy for mCRC and discuss current and future opportunities in this field.

TARGETING ANGIOGENESIS IN MCRC

Targeting Angiogenesis in the First-Line Setting Bevacizumab, a vascular endothelial growth factor A (VEGF-A) –targeting monoclonal anti-

body, is the only antiangiogenic agent approved by the US Food and Drug Administration for the firstline treatment of mCRC. This approval was based on a randomized phase III clinical trial (AVF2107; A Study to Evaluate Avastin in Combination With Standard Chemotherapy to Treat Colorectal Cancer) of IFL (irinotecan, fluorouracil, and leucovorin [given as a bolus injection rather than as an infusion over 48 hours]). That trial compared IFL with IFL plus bevacizumab, which showed superior response rate (RR), progression-free survival (PFS), and overall survival (OS) for patients on the IFL plus bevacizumab arm (Table 1).6 Several subsequent phase III randomized clinical trials failed to show a survival advantage when bevacizumab was integrated into the first-line treatment of mCRC (Table 1).7-11 However, a consistent improvement in PFS was noted and was most pronounced in the setting of fluoropyrimidine therapy.10,11 A discrepancy in OS seen between the AVF2107 study and subsequent studies may be partly attributed to the continuation of bevacizumab after first progression on the experimental arm of the AV2107 study. It is also possible that the advantages obtained from the addition of bevacizumab are more pronounced in the context of less effective combination treatments or with fluoropyrimidine monotherapy. Indeed, lower hazard ratios for progression were noted when bevacizumab was combined with the therapy being given in control arms associated with a PFS of less than 7 months (Table 1). Because of the clinical efficacy © 2015 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on April 29, 2015 Copyright © 2015 Americanfrom Society of Clinical Oncology. All rights reserved. 128.122.253.212

Copyright 2015 by American Society of Clinical Oncology

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© 2015 by American Society of Clinical Oncology Study Design

Control Arm

Arm A: bolus fluorouracil/ leucovorin ⫹ irinotecan ⫹ bevacizumab every 3 weeks

IFL ⫹ bevacizumab

Experimental Arm(s)

Primary: RR; secondary: OS

Primary: OS; secondary: RR, PFS

Efficacy Objectives

Randomized phase Capecitabine III clinical trial in patients age ⱖ 70 years; 1:1 randomization; N ⫽ 280

Capecitabine ⫹ bevacizumab

Key Toxicities

PFS: 9.1 months (bevacizumab arm) v 5.1 months (control) (HR, 0.53; P ⬍ .001)

PFS: 9.2 months (bevacizumab arm) v 8.4 months (control) (HR, 0.88; P ⫽ .265)

OS: 20.6 months (bevacizumab arm) v 20.6 months (control) (HR, 1.18; P ⫽ .278); RR: 54.2% (bevacizumab arm) v 48.1% (control) (P ⫽ .286) RR: 19% (bevacizumab arm) v 10% (control) (P ⫽ .04); OS: 20.7 months (bevacizumab arm) v 16.8 months (control) (HR, 0.79; P ⫽ .18)

Higher rate of ATE, VTE, hypertension, and proteinuria on the bevacizumab arm

Increased hypertension, proteinuria, bleeding, and asthenia on the bevacizumab arm

RR: 44.8% (IFL ⫹ Grade 3 hypertension bevacizumab) v 34.8% 11% on the (IFL) (P ⬍ .001); PFS: bevacizumab arm 10.6 months (IFL ⫹ bevacizumab) v 6.2 months (IFL) (HR, 0.54; P ⬍ .001)

Other Efficacy End Points

Postprogression Treatment

37% of patients received second-line treatment

Not reported

Postprogression treatment was received in approximately 50% of patients. Patients on the IFL ⫹ bevacizumab arm were allowed to continue bevacizumab in the second-line setting RR: 36.8% (arm A) v PFS: not reported; OS: 22 Increased grade 3 to 4 Patients were switched to 35.2% (arm B) months (arm A) v 25 hypertension (22%) bolus fluorouracil ⫹ months (arm B) and proteinuria oxaliplatin every 3 (P ⫽ .13) (6%) on the weeks upon bevacizumab arm progression. Rate of second-line therapy was not reported PFS: 9.4 months OS: 21.3 months Increased number of No difference in second(bevacizumab arms) v (bevacizumab arms) v patients with ATE, line treatment rates 8 months (control) 19.9 months (control) VTE, perforation, (HR, 0.83; P ⫽ .0023) (HR, 0.89; P ⫽ .077); bleeding, fistula, RR: 38% (bevacizumab and hypertension arms) v 38% (control) on the bevacizumab arm

Primary Efficacy End Point

OS: 20.3 months (IFL bevacizumab) v 15.6 months (IFL) (HR, 0.66; P ⬍ .001)

(continued on following page)

Primary: PFS; secondary: RR, OS

NO16966/A Study Randomized phase XELOX and FOLFOX XELOX ⫹ bevacizumab; Primary: PFS; of Capecitabine III clinical FOLFOX ⫹ secondary: RR, (Xeloda) As a trial 2 ⫻ 2 bevacizumab OS First-line Therapy factorial design; in Patients With N ⫽ 1,401 Metastatic Colorectal Cancer ITACa/Sequential Randomized phase FOLFOX4 or FOLFIRI FOLFOX4 ⫹ Primary: PFS; Treatment III clinical trial; bevacizumab; secondary: RR, Strategy for 1:1 FOLFIRI ⫹ OS Metastatic randomization; bevacizumab Colorectal N ⫽ 376 Cancer

Randomized phase Arm B: bolus III clinical fluorouracil/ trial; 1:1 leucovorin ⫹ randomization; irinotecan every 3 N ⫽ 222 weeks

AVF2017/A Study to Randomized phase IFL Evaluate Avastin III clinical in Combination trial; 1:1 With Standard randomization; Chemotherapy to N ⫽ 813 Treat Colorectal Cancer

Study Acronym/Title

Cunningham et al10 AVEX/Bevacizumab (Avastin) in Combination With Capecitabine (Xeloda) in Elderly Patients With Metastatic Colorectal Cancer

Passardi et al9

Saltz et al8

Stathopoulos et al7

First-line bevacizumabbased phase III studies Hurwitz et al6

Reference

Table 1. Angiogenesis Targeting in mCRC Studies

Marwan G. Fakih



www.jco.org Control Arm

Randomized phase FOLFIRI ⫹ III clinical bevacizumab trial; 1:1 randomization; N ⫽ 508

Randomized phase Capecitabine III clinical trial; 1:1:1 randomization; N ⫽ 471

Study Design

CAIRO3/ Randomized phase Treatment Maintenance III clinical trial; interruption until Treatment N ⫽ 558 progression Versus following six Observation cycles of After Induction in CAPOX ⫹ Advanced bevacizumab Colorectal Carcinoma

TRIBE/Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer

MAX/Mitomycin C, Avastin, and Xeloda in Patients With Untreated Metastatic Colorectal Cancer

Study Acronym/Title

Antiangiogenic clinical trials in secondline treatment Giantonio et al18 ECOG 3200/ Second-line FOLFOX4 Combination randomized Chemotherapy phase III clinical With or Without trial in patients Bevacizumab for whom Compared With fluoropyrimidine Bevacizumab and irinotecan Alone in Treating therapy failed Patients With (bevacizumabAdvanced or naïve); 1:1:1 Metastatic randomization; Colorectal Cancer N ⫽ 829 That Has Been Previously Treated

Koopman et al14,15

Loupakis et al13

Tebbutt et al11

Reference

FOLFOX4 ⫹ bevacizumab; bevacizumab


Primary Efficacy End Point Other Efficacy End Points

Key Toxicities

Primary: OS; OS: 12.9.months secondary: PFS, (FOLFOX4 ⫹ RR bevacizumab) v 10.8 months (FOLFOX4) (HR, 0.75; P ⫽ .001)

PFS: 7.3 months Hypertension, bowel (FOLFOX4 ⫹ perforation, and bevacizumab) v 4.7 bleeding on the months (FOLFOX4) bevacizumab arm (HR, 0.61; P ⬍ .001); bevacizumab PFS: 2.7 months; RR: 22.7% (FOLFOX4 ⫹ bevacizumab) v 8.6% (FOLFOX4) (P ⬍ .001); bevacizumab RR: 3.3%

PFS: 8.5 months RR: 38.1% (capecitabine ⫹ Increased ATE, (capecitabine ⫹ bevacizumab) v 30.3% hypertension, and bevacizumab) v 5.7 (capecitabine); OS: 18.9 proteinuria on the months (capecitabine) months (capecitabine ⫹ bevacizumab arms (HR, 0.63; P ⫽ .01); bevacizumab) v 18.9 PFS: 8.4 months months (capecitabine) (capecitabine ⫹ (HR, 0.875; P ⫽ .314) mitomycin ⫹ bevacizumab) v 5.7 months (capecitabine) (HR, 0.557; P ⫽ .01) Primary: PFS; PFS: 12.1 months RR: 65% (FOLFOXIRI ⫹ Increased diarrhea, secondary: RR, (FOLFOXIRI ⫹ bevacizumab) v 53% stomatitis, OS bevacizumab) v 9.7 (FOLFIRI ⫹ neuropathy, and months (FOLFIRI ⫹ bevacizumab) (P ⫽ neutropenia on the bevacizumab) (HR, .006); OS: 31 months FOLFOXIRI ⫹ 0.75; P ⫽ .003) (FOLFOXIRI ⫹ bevacizumab arm bevacizumab) v 25.8 months (FOLFIRI ⫹ bevacizumab) (HR, 0.79; P ⫽ .054) Primary: PFS2 PFS2: 11.7 months PFS1: 8.5 months Quality of life (defined as TTP (maintenance arm) v (maintenance arm) v 4.1 noninferior on the from CAPOX 8.5 months months (observation arm) maintenance arm re-challenge after (observation arm) (HR, 0.39; P ⬍ .001); compared with the first progression); (HR, 0.64; P ⬍ .001) TTP2: 13.9 months observation arm secondary: PFS1 (maintenance arm) v 11.1 (first months (observation arm) progression), (HR, 0.68; P ⬍ .001); OS: TTP2 (time to 21.6 months second (maintenance arm) v 18.1 progression), OS months (observation) (HR, 0.83; P ⫽ .22)


Efficacy Objectives

(continued on following page)

Maintenance capecitabine ⫹ bevacizumab following six cycles of CAPOX ⫹ bevacizumab

FOLFOXIRI ⫹ bevacizumab

Capecitabine ⫹ bevacizumab; capecitabine ⫹ mitomycin-C ⫹ bevacizumab

Experimental Arm(s)

Table 1. Angiogenesis Targeting in mCRC Studies (continued)

Not reported

Treatment beyond first progression was given to 67% of the observation and 64% of the maintenance arm.

Second-line therapy was received by 68% of the control arm and 66% of the experimental arm.

Poststudy salvage chemotherapy was given in 68% of the capecitabine arm, 62% of the capecitabine ⫹ bevacizumab arm, and 61% of the capecitabine ⫹ bevacizumab ⫹ mitomycin arm.


Targeted Approaches to Metastatic Colorectal Cancer


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Study Design

Control Arm

CORRECT/A Randomized phase BSC Randomized, III clinical trial in Double Blind, refractory Placebometastatic Controlled Phase colorectal III Study of cancer (all Regorafenib Plus active BSC in Patients treatments With Metastatic failed); 2:1 Colorectal randomization; Cancer Who N ⫽ 760 Have Progressed After Standard Therapy

ML18147/A Study Second-line Alternate of Avastin randomized combination (Bevacizumab) phase III clinical chemotherapy Plus Crossover trial in patients Fluoropyrimidinewho progressed Based on one line of Chemotherapy in fluoropyrimidinePatients With based Metastatic combination Colorectal chemotherapy ⫹ Cancer bevacizumab; 1:1 randomization; N ⫽ 820 VELOUR/ Second-line FOLFIRI Aflibercept randomized Versus Placebo phase III clinical in Combination trial in patients With Irinotecan who and 5-FU in the progressed Treatment of following one Patients With line of Metastatic oxaliplatin and Colorectal fluoropyrimidine; Cancer After N ⫽ 1,226 Failure of an Oxaliplatin Based Regimen

Study Acronym/Title

Regorafenib

FOLFIRI ⫹ ziv-aflibercept

Alternate combination chemotherapy ⫹ bevacizumab

Experimental Arm(s)


Primary: OS; secondary: PFS

OS: 6.4 months (regorafenib) v 5.0 months (BSC) (HR, 0.77; P ⫽ .0052)

Primary: OS; OS: 13.5 months secondary: PFS, (FOLFIRI ⫹ zivRR aflibercept) v 12.06 months (FOLFIRI) (HR, 0.817; P ⫽ .0032); only 30% of patients enrolling onto this study had prior bevacizumab

Primary: OS; OS: 11.2 months secondary: PFS, (chemotherapy ⫹ RR bevacizumab) v 9.8 months (chemotherapy) (HR, 0.81; P ⫽ .0062)

Efficacy Objectives

Key Toxicities


PFS: 1.9 months (regorafenib) v 1.7 months (BSC) (HR, 0.49; P ⬍ .001); RR: 1% (regorafenib)

Regorafenib: increased fatigue, rash, hand-foot syndrome, diarrhea, anorexia, hypertension, and mucositis; ⬎ 70% required at least one dose interruption

Not reported

PFS: 6.9 months (FOLFIRI ⫹ In addition to the Not reported ziv-aflibercept) v 4.7 increased months (FOLFIRI) (HR, antiangiogenesis0.758; P ⬍ .001); RR: associated 19.8% (FOLFIRI ⫹ zivtoxicities, zivaflibercept) v 11.1% aflibercept (FOLFIRI) (P ⬍ .001) increased the rates of diarrhea, asthenia, stomatitis, infections, handfoot syndrome, and severe neutropenia

PFS: 5.7 months Increased bleeding, Subsequent therapy given (chemotherapy ⫹ VTE, and in 69% of the bevacizumab) v 4.1 perforation in the bevacizumab arm and months (chemotherapy) bevacizumab arm; 68% of the (HR, 0.68; P ⬍ .001); no difference noted chemotherapy arm RR: 5.4% in other toxicities (chemotherapy ⫹ bevacizumab) v 3.9% (chemotherapy)


Abbreviations: ATE, arterial thrombotic event; BSC, best supportive care; CAPOX, capecitabine plus oxaliplatin; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; FOLFOXIRI, fluorouracil, leucovorin, oxaliplatin, and irinotecan; HR, hazard ratio; IFL, irinotecan, fluorouracil, and leucovorin; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; RR, response rate; TTP, time to progression; VTE, venous thrombotic event; XELOX, capecitabine plus oxaliplatin.

Antiangiogenic therapy in the treatment of refractory disease Grothey et al17

Van Cutsem et al16

Bennouna et al12

Reference

Table 1. Angiogenesis Targeting in mCRC Studies (continued)

Marwan G. Fakih



associated with bevacizumab across fluoropyrimidine-based studies, it has become an acceptable standard across all first-line fluoropyrimidine-based treatments.8,10,13,19 It is also recommended that patients continue on fluoropyrimidine and bevacizumab until progression, even after the completion of an intended induction phase of combination therapy (Table 1).14 Scheduled treatment breaks after first-line combination therapy have been associated with a shorter PFS; however, mixed results have been reported on the impact of this strategy on OS.15,20,21 Targeting Angiogenesis in Second-Line and Subsequent Line Settings Eastern Cooperative Oncology Group (ECOG) 3200 (Combination Chemotherapy With or Without Bevacizumab Compared With Bevacizumab Alone in Treating Patients With Advanced or Metastatic Colorectal Cancer That Has Been Previously Treated) demonstrated an RR, PFS, and OS advantage from the addition of bevacizumab to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy in bevacizumab-naive patients with mCRC after first-line progression on fluorouracil and irinotecan (Table 1).18 The ML18147 (A Study of Avastin [Bevacizumab] Plus Crossover FluoropyrimidineBased Chemotherapy in Patients With Metastatic Colorectal Cancer) study evaluated the utility of continuing bevacizumab beyond first progression into the second-line treatment of mCRC.12 In that study, patients who had progressive disease while receiving first-line bevacizumab plus combination chemotherapy were randomly assigned to an alternate combination chemotherapy with or without bevacizumab. A modest but statistically significant improvement in PFS and OS was noted on the bevacizumab arm, confirming that there is a treatment advantage to continuing angiogenesis inhibition in mCRC (Table 1). The VELOUR (Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen) study compared ziv-aflibercept—a VEGF-A-, VEGF-B-, and placental growth factor– binding recombinant fusion protein—in combination with FOLFIRI to FOLFIRI plus placebo in patients with mCRC who had progressed on first-line oxaliplatin-fluoropyrimidine therapy (Table 1).16 Modest improvements in PFS and OS were noted, but patients experienced significant additional toxicities, limiting the adoption of this agent in mCRC in the United States. The only randomized phase III clinical trial to investigate and report on the value of angiogenesis inhibition in chemotherapy refractory settings tested the multitargeted tyrosine kinase inhibitor regorafenib against placebo (Table 1).17 Regorafenib reduced the likelihood of progression and improved OS from a median of 5 to 6.4 months. This clinically modest improvement in OS came at a substantial cost in terms of skin toxicity, GI toxicity, and constitutional symptoms. These studies indicate that there is a real but modest value to the continuation of angiogenesis inhibition in managing CRC across lines of treatment. Bevacizumab can be considered in the first- and secondline fluoropyrimidine-based treatment of mCRC. Ziv-aflibercept is an alternative to bevacizumab when combined with FOLFIRI, but only in second-line settings. Regorafenib use should be limited to patients who progressed on all standard therapies. www.jco.org

TARGETING EGFR IN MCRC

Targeting EGFR in Chemotherapy Refractory Settings Cetuximab was initially approved on the basis of the BOND clinical trial, which compared cetuximab plus irinotecan with cetuximab alone in patients with fluoropyrimidine- and irinotecanresistant mCRC.22 RR and PFS for the combination arm were superior to cetuximab only. Subsequently, the NCI-CO17 (Cetuximab and Best Supportive Care Compared With Best Supportive Care Alone in Treating Patients With Metastatic EGFR-Positive Colorectal Cancer) study confirmed an advantage for cetuximab in all efficacy end points over best supportive care in chemotherapy-resistant mCRC (Table 2). 23 A follow-up efficacy analysis was performed on the basis of activating KRAS mutation status. KRAS mutation assessment was limited to codons 12 and 13 of exon 2.24 Clinical benefit was limited to the KRAS wild-type (KRAS-wt [exon 2]) population, with a doubling of OS when patients were treated with cetuximab in comparison with best supportive care.24 The predictive value of KRAS for benefit from anti-EGFR monotherapy was similarly confirmed in the setting of panitumumab monotherapy.33 In addition, panitumumab was noninferior to cetuximab in a phase III clinical trial in patients with chemotherapy-resistant KRAS-wt mCRC (Table 2).26 Targeting EGFR in Second-Line Settings Three large randomized phase III clinical trials investigated the addition of an anti-EGFR agent in the second-line treatment of mCRC (Table 2). All three studies confirmed an improvement in RR and PFS, but this failed to translate into an OS advantage.28,29,34 The EPIC trial was conducted before the establishment of KRAS as a predictive marker and was therefore significantly underpowered to test an OS end point in KRAS-wt patients.34 Both the 20050181 (Comparison of Treatment Effect of Chemotherapy With Panitumumab to Chemotherapy Alone) and the PICCOLO (Panitumumab, Irinotecan and Ciclosporin in Colorectal Cancer Therapy; Irinotecan With or Without Panitumumab) trials were powered to address PFS in a KRAS-wt population.28,29 The lack of benefit in OS may be attributed to salvage with anti-EGFR– containing regimens on the control arms of the EPIC and 20050181 studies. Alternatively, accelerated post-treatment progression may have occurred on the anti-EGFR arms and was possibly related to a more aggressive tumor phenotype after anti-EGFR withdrawal.29 Targeting EGFR in First-Line Settings The NORDIC (FLOX, Given Continuously or Intermittently, in Combination With Cetuximab in the First Line Treatment of Metastatic Colorectal Cancer) and COIN (Continuous Chemotherapy Plus Cetuximab, or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First-Line Treatment of Metastatic Colorectal Cancer) trials initially cast doubts on the benefits of adding cetuximab to oxaliplatin-based regimens (Table 2).30,31 The COIN study allowed for the physician’s choice of FOLFOX or XELOX with subsequent random assignment to cetuximab versus no cetuximab. Excessive toxicities were noted on the XELOX plus cetuximab arm, which explains the lack of benefit in that cohort of patients. A positive effect on PFS was noted in the FOLFOX cohort. The NORDIC trial used a © 2015 by American Society of Clinical Oncology


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Study Acronym/Title

Phase III first-line antiEGFR studies Maughan et al30 COIN/Continuous Chemotherapy Plus Cetuximab, or Intermittent Chemotherapy With Standard Continuous Palliative Combination Chemotherapy With Oxaliplatin and a Fluoropyrimidine in First-Line Treatment of Metastatic Colorectal Cancer Tveit et al31 NORDIC VII/FLOX, Given Continuously or Intermittently, in Combination With Cetuximab in the First Line Treatment of Metastatic Colorectal Cancer Douillard et al27,32 PRIME/The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy

Reference

Control Arm

Experimental Arm(s)

Efficacy Objectives


Randomized phase III clinical trial; N ⫽ 1,183; KRAS exon 2 wt: n ⫽ 656; RAS-wt (KRAS and NRAS): n ⫽ 512

Randomized phase III clinical trial; 1:1:1 randomization; N ⫽ 566

FOLFOX4




Key Toxicities


KRAS exon 2 wt: OS: 23.8 Increased skin toxicity, months (FOLFOX4 ⫹ GI toxicity, and panitumumab) v 19.4 months hypomagnesemia (FOLFOX4) (HR, 0.83; noted on the P ⫽ .03) panitumumab arm RR: 55% (FOLFOX4 ⫹ panitumumab) v 48% (FOLFOX4) (OR, 1.35; P ⫽ .068) RAS-wt: OS: 25.8 months (FOLFOX4 ⫹ panitumumab) v 20.2 months (FOLFOX4) (HR, 0.77; P ⫽ .009) RAS-wt and BRAF-wt: OS: 28.3 months (FOLFOX4 ⫹ panitumumab) v 20.9 months (FOLFOX4) (HR, 0.74; P ⫽ .02)

KRAS-wt: PFS: 7.9 KRAS-wt: RR: 49% (arm B) v Cetuximab was months (arm B) v 41% (arm A) (P ⫽ .15); no associated with 8.6 months (arm A) difference in OS was noted increased rates of (HR, 1.06; P ⫽ .66) among all 3 arms (arm A, 22 skin and GI toxicities months; arm B, 20.1 months; arm C, 21.4 months)

Subsequent chemotherapy was received in 62% of the FOLFOX4 arm and 53% of the FOLFOX4 ⫹ panitumumab arm; subsequent antiEGFR therapy was received in 18% of the FOLFOX4 arm and 8% of the FOLFOX4 ⫹ panitumumab arm

Subsequent treatment was received in 73.5% of arm A, 75.8% of arm B, and 64.2% of arm C

KRAS-wt: OS: 17 BRAF-mut: OS: 7.2 months (arm Cetuximab administration Increased rate of months (arm B) v B) v 10 months (arm A) (HR, was associated with a second-line 17.9 months (arm 1.18; P ⫽ .46) decrease in dose therapy in the A) (HR, 1.04; KRAS-wt: PFS: 8.6 months intensity and with control arm v the P ⫽ .67) (arms A and B) (HR, 0.96; increased skin and GI cetuximab arm; KRAS, NRAS, and P ⫽ .6) toxicities 65% (arm A) v BRAF-wt: OS: 19.9 PFS HR for the FOLFOX arm 54% (arm B) months (arm B) v favored cetuximab (HR, 0.72; (P ⫽ .0061) 20.1 months (arm P ⫽ .037). No benefit in PFS A) (HR, 1.02; P ⫽ was noted on the cetuximab ⫹ .86) XELOX arm compared with the XELOX arm; RR, 64% (arm B) v 57% (arm A) (OR, 1.35; P ⫽ .045)


KRAS exon 2 wt: PFS: 9.6 months (FOLFOX4 ⫹ panitumumab) v 8 months (FOLFOX4) (HR, 0.8; P ⫽ .02) RAS-wt: PFS: 10.8 months (FOLFOX4 ⫹ panitumumab) v 9.2 months (FOLFOX4) (HR, 0.72; P ⫽ .004) RAS-wt and BRAF-wt: PFS: 10.1 months (FOLFOX4 ⫹ panitumumab) v 7.9 months (FOLFOX4) (HR, 0.68; P ⫽ .002) (continued on following page)

FOLFOX4 ⫹ panitumumab

Arm A: FLOX (bolus Arm B: FLOX ⫹ fluorouracil, cetuximab leucovorin, and Arm C: intermittent oxaliplatin) FLOX ⫹ cetuximab

Randomized phase III Arm A: oxaliplatin ⫹ Arm B: oxaliplatin ⫹ Primary: OS; clinical trial; 1:1:1 fluoropyrimidine fluoropyrimidine ⫹ secondary: randomization; (FOLFOX or cetuximab RR, PFS N ⫽ 2,445 XELOX) Arm C: intermittent Arm A: n ⫽ 815 (367 oxaliplatin ⫹ KRAS-wt) fluoropyrimidine Arm B: n ⫽ 815 (362 regimen KRAS-wt) KRAS mutation defined as mutation in codons 12, 13, and 61

Study Design

Table 2. EGFR Targeting in mCRC

Marwan G. Fakih



www.jco.org Study Design

Second-line randomized phase III clinical trial in patients for whom fluoropyrimidine and oxaliplatin therapy failed; 1:1 randomization; N ⫽ 1,186; KRAS exon 2 wt: n ⫽ 597; RAS-wt: n ⫽ 421

CRYSTAL/Cetuximab Randomized phase III Combined With clinical trial; 1:1 Irinotecan in randomization; N ⫽ First-Line 1,198; KRAS exon 2 Therapy for wt: n ⫽ 676; RAS-wt: Metastatic n ⫽ 367 Colorectal Cancer

Study Acronym/Title

Phase III second-line anti-EGFR clinical trials Peeters et al28 20050181/ Comparison of Treatment Effect of Chemotherapy With Panitumumab to Chemotherapy Alone

Van Cutsem et al25

Reference

FOLFIRI

FOLFIRI

Control Arm

Primary: PFS; secondary: OS

Primary: PFS; secondary: OS

Efficacy Objectives KRAS exon 2 wt: PFS: 9.9 months (FOLFIRI ⫹ cetuximab) v 8.4 months (FOLFIRI) (HR, 0.696; P ⫽ .0012) RAS-wt: PFS: 11.4 months (FOLFIRI ⫹ cetuximab) v 8.4 months (FOLFIRI) (HR, 0.56; P ⬍ .001) BRAF-mut: PFS: 8 months (FOLFIRI ⫹ cetuximab) v 5.6 months (FOLFIRI) (HR, 0.934; P ⫽ .87)


KRAS exon 2 wt: PFS: 5.9 months (FOLFIRI ⫹ panitumumab) v 3.9 months (FOLFIRI) (HR, 0.73; P ⫽ .004) RAS-wt: PFS: 6.4 months (FOLFIRI ⫹ panitumumab) v 4.6 months (FOLFIRI) (HR, 0.7; P ⫽ .007) RAS-wt and BRAF-wt: PFS: 6.9 months (FOLFIRI ⫹ panitumumab) v 5.5 months (FOLFIRI) (HR, 0.68; P ⫽ .006) (continued on following page)

FOLFIRI ⫹ panitumumab

FOLFIRI ⫹ cetuximab

Experimental Arm(s)

Table 2. EGFR Targeting in mCRC (continued)

Increased skin toxicity, GI toxicity, hypomagnesemia, and hypersensitivity reactions on the cetuximab arm

Key Toxicities

KRAS exon 2 wt: subsequent line(s) of treatment were received in 66.1% (10.8% anti-EGFR) on the FOLFIRI ⫹ cetuximab arm v 71.7% (30.9% anti-EGFR) on the FOLFIRI arm


KRAS exon 2 wt: OS: 14.5 Increased skin, GI Subsequent antimonths (FOLFIRI ⫹ toxicity, and EGFR therapy in panitumumab) v 12.5 months hypomagnesemia on 10% of the (FOLFIRI) (HR, 0.85; P ⫽ .12) the panitumumab arm FOLFIRI ⫹ RR: 35% (FOLFIRI ⫹ panitumumab arm panitumumab) v 10% v 31% in the (FOLFIRI) (P ⬍ .001) FOLFIRI arm; RAS-wt: OS: 16.2 months chemotherapy (FOLFIRI ⫹ panitumumab) v post-progression 13.9 months (FOLFIRI) (HR, was used in 47% 0.81; P ⫽ .08) of the FOLFIRI ⫹ RR: 41% (FOLFIRI ⫹ panitumumab arm panitumumab) v 10% and in 48% of the (FOLFIRI) FOLFIRI arm RAS-wt and BRAF-wt: OS: 18.7 months (FOLFIRI ⫹ panitumumab) v 15.4 months (FOLFIRI) (HR, 0.83; P ⫽ .15)

KRAS exon 2 wt: OS: 23.5 months (FOLFIRI ⫹ cetuximab) v 20.2 months (FOLFIRI) (HR, 0.797; P ⫽ .0093) RR: 57.3% (FOLFIRI ⫹ cetuximab) v 39.7% (FOLFIRI) (OR, 2.069; P ⬍ .001) RAS-wt: OS: 28.4 months (FOLFIRI ⫹ cetuximab) v 20.2 months (FOLFIRI) (HR, 0.69; P ⫽ .0024) RR: 66.3% (FOLFIRI ⫹ cetuximab) v 38.6% (FOLFIRI) (OR, 3.11; P ⬍ .001) BRAF-mut: OS: 14.1 months (FOLFIRI ⫹ cetuximab) v 10.3 months (FOLFIRI) (HR, 0.908; P ⫽ .74) RR: 19.2% (FOLFIRI ⫹ cetuximab) v 15.2% (FOLFIRI) (OR, 1.084; P ⫽ .91)





7

8


Information downloaded from jco.ascopubs.org and provided by at NEW YORK UNIVERSITY MED CTR on April 29, 2015 Copyright © 2015 Americanfrom Society of Clinical Oncology. All rights reserved. 128.122.253.212 Control Arm

Cetuximab

BSC

Second-line randomized Irinotecan (300-350 phase III clinical trial in mg/m2 once patients who every 3 weeks) progressed on one line of fluoropyrimidinebased chemotherapy; 1:1:1 randomization (irinotecan v irinotecan ⫹ panitumumab v irinotecan ⫹ cyclosporin); N ⫽ 1,198 KRAS-wt (codon 12, 13, 61) n ⫽ 460 allocated to irinotecan with or without panitumumab

Study Design

NCI-CO17/Cetuximab Randomized phase III and Best clinical trial in Supportive Care chemotherapyCompared With resistant or Best Supportive chemotherapyCare Alone in intolerant mCRC; 1:1 Treating Patients randomization; N ⫽ With Metastatic 572 EGFR-Positive KRAS-wt exon 2, Colorectal n ⫽ 230 Cancer ASPECCT/A Study Randomized phase III of Panitumumab noninferiority clinical Efficacy and trial in KRAS-wt exon Safety Compared 2 patients with to Cetuximab in chemotherapyPatients With resistant or KRAS Wild-Type chemotherapyMetastatic intolerant metastatic Colorectal colorectal cancer; 1:1 Cancer randomization; N ⫽ 1,010

PICCOLO/ Panitumumab, Irinotecan and Ciclosporin in Colorectal Cancer Therapy; Irinotecan With or Without Panitumumab

Study Acronym/Title

Panitumumab

Cetuximab

Irinotecan ⫹ panitumumab (9 mg/kg once every 3 weeks)

Experimental Arm(s)

Primary: OS; secondary: PFS, RR



Efficacy Objectives Other Efficacy End Points

Key Toxicities

OS: 10.4 months (panitumumab) v 10 months (cetuximab) Panitumumab estimated to maintain 105.7% of the effects of cetuximab, with the minimum preservation of cetuximab treatment effect (lower 95% boundary) 81.9%

KRAS-wt: OS: 9.5 months (cetuximab) v 4.8 months (BSC) (HR, 0.55; P ⬍ .001)

Increased skin toxicity Not reported on the cetuximab arm

Only 6% of the irinotecan group received subsequent antiEGFR therapy


PFS: 4.1 months (panitumumab) Increased Postprogression v 4.4 months (cetuximab) hypersensitivity on therapy was 41% (HR, 1.0; 85% CI, 0.88 to the cetuximab arm; in the 1.14) increased panitumumab arm RR: 22% (panitumumab) v hypomagnesemia on v 42% in the 19.8% (cetuximab) the panitumumab arm cetuximab arm

KRAS-wt: PFS: 3.7 months (cetuximab) v 1.9 months (BSC) (HR, 0.40; P ⬍ .001) RR: 12.8% (cetuximab) v 0% (BSC)

KRAS-wt: OS: 10.4 KRAS-wt: PFS: panitumumab ⫹ Increased diarrhea, skin months (irinotecan ⫹ irinotecan arm was superior toxicity, lethargy, panitumumab) v to irinotecan (HR, 0.78; P ⫽ infection, and 10.9 months .015) hematologic toxicity (irinotecan) (HR, RR: 33% (panitumumab ⫹ on the irinotecan ⫹ 1.01; P ⫽ .91) irinotecan) v 12% (irinotecan) panitumumab arm (OR, 4.12; P ⬍ .001)


Abbreviations: BSC, best supportive care; EGFR, epidermal growth factor receptor; FLOX, fluorouracil, leucovorin, oxaliplatin; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; FOLFOX4, infusional fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; mCRC, metastatic colorectal cancer; mut, mutated; OR, odds ratio; OS, overall survival; PFS, progression-free survival; RR, response rate; wt, wild type; XELOX, capecitabine plus oxaliplatin.

Price et al26

Phase III anti-EGFR studies in chemotherapyresistant disease Karapetis et al24

Seymour et al29

Reference

Table 2. EGFR Targeting in mCRC (continued)

Marwan G. Fakih



nonconventional oxaliplatin-fluoropyrimidine regimen (bolus fluorouracil), and no benefit was seen when cetuximab was added to this combination.31 The PRIME (The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) clinical trial, conversely, demonstrated convincing evidence of improvements in PFS and OS when panitumumab was added to FOLFOX chemotherapy in KRAS-wt patients, whereas a detriment was noted in patients with a KRAS mutation (KRAS-mut; Table 2).32 The PFS benefits in the PRIME trial were in line with those in the FOLFOX arm on the COIN study and do not suggest a differential impact of panitumumab over cetuximab in a FOLFOX setting. The CRYSTAL (Cetuximab Combined With Irinotecan in FirstLine Therapy for Metastatic Colorectal Cancer) phase III study investigated the addition of cetuximab to FOLFIRI. Cetuximab addition improved RR, PFS, and OS (Table 2).25 These data, in aggregate, support a benefit from the addition of either cetuximab or panitumumab to the first-line treatment of mCRC. No definitive preferred backbone of chemotherapy can be identified from these studies. KRAS and RAS Mutations in mCRC Activating KRAS mutations in exon 2 occur in approximately 37% to 45% of CRCs.25,27,28,30,31 Considerable debate has occurred regarding the predictive value of individual exon 2 KRAS-mut in mCRC. Although some reports have suggested a possible but limited clinical benefit from anti-EGFR therapy for patients with codon 13 (G13D) mutations,35,36 a meta-analysis of three randomized phase III clinical trials of panitumumab in first-line, second-line, and refractory settings failed to confirm these findings.37 In addition to exon 2 KRASmut, an additional 9% to 10% of patients with CRC carry non-KRAS exon 2 RAS mutations. These include 4% to 5% with NRAS-mut (codons 12 or 13 in exon 2 and codons 59 or 61 in exon 3) and 5% with a non– exon 2 KRAS-mut (codons 59 or 61 in exon 3, and codons 117 or 146 in exon 4).27 For patients with activating non– exon 2 KRASmut and NRAS-mut, no benefit, and sometimes a detrimental effect, was noted with the addition of anti-EGFR therapy to various chemotherapy backbones across first-line, second-line, and refractory therapy.27,38,39 On the basis of these findings, anti-EGFR therapy should be excluded from the treatment of any patient with RAS mutations (exon 2, 3, or 4 of KRAS or NRAS). BRAF Mutations in mCRC BRAF (V600E) mutations occur in approximately 5% of patients with mCRC and are associated with a more aggressive CRC phenotype, chemotherapy resistance, and an inferior OS.25,30,31,44 Although the negative prognostic impact of BRAF-mut has been confirmed across several studies (Table 2), debate continues regarding its value as a predictive marker of response to anti-EGFR therapy. Because constitutive BRAF activity evades any upstream EGFR inhibition, it has been postulated that EGFR inhibition would have limited clinical activity in this setting. Indeed, no objective responses have been reported for panitumumab or cetuximab monotherapy in BRAF-mut mCRC.45 In the second-line treatment of mCRC, the PICCOLO trial reported on a subgroup of 131 patients with BRAF-mut mCRC randomly assigned to second-line panitumumab plus irinotecan or irinotecan alone.29 Patients with BRAF-mut had a trend toward worse OS with the addition of panitumumab (hazard ratio, 1.4; 95% CI, 0.82 to 2.39). In a recent update, the 20050181 study reported dismal outwww.jco.org

comes in the BRAF-mut mCRC population for both the second-line FOLFIRI-panitumumab and FOLFIRI arms (median OS of 4.7 and 5.7 months, respectively).46 In the first-line setting, a combined analysis of the CRYSTAL and OPUS (Oxaliplatin and Cetuximab in FirstLine Treatment of Metastatic Colorectal Cancer) studies showed that the addition of cetuximab led to a nonsignificant positive trend in RR, PFS, and OS. However, no improvement in efficacy was reported with the addition of cetuximab or panitumumab to FOLFOX in the PRIME or the COIN studies. These studies, in aggregate, suggest lack of a clinically meaningful improvement in OS when anti-EGFR therapy is used, whether as monotherapy or in combination with chemotherapy in BRAF-mut mCRC. Given the aggressive behavior of BRAF-mut mCRC, consideration should be made for initial therapy with first-line fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) plus bevacizumab. This combination has been associated with an RR of 73%, a PFS of 9.2 months, and an OS of 24.1 months in a small prospective phase II clinical trial.47 In addition, the TRIBE (Combination Chemotherapy and Bevacizumab as First-Line Therapy in Treating Patients With Metastatic Colorectal Cancer) clinical trial reported a more favorable outcome in terms of median PFS and OS for FOLFOXIRI-bevacizumab over FOLFIRI-bevacizumab in the BRAF-mut subgroup.13 FIRST-LINE ANTI-EGFR THERAPY VERSUS BEVACIZUMAB IN RAS-WT MCRC

The FIRE-3 (5-FU, Folinic Acid and Irinotecan [FOLFIRI] Plus Cetuximab Versus FOLFIRI Plus Bevacizumab in First Line Treatment Colorectal Cancer [CRC]) and Cancer and Leukemia Group B (CALGB) 80405 (Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer) phase III clinical trials compared cetuximab with bevacizumab whereas the PEAK (Panitumumab Efficacy in Combination With mFOLFOX6 Against Bevacizumab Plus mFOLFOX6 in mCRC Subjects With Wild-Type KRAS Tumors) randomized phase II clinical trial compared panitumumab with bevacizumab in the first-line treatment of KRAS-wt exon 2 mCRC (Table 3).38,39,40 The primary end point of FIRE-3 was RR; PFS and OS were secondary end points. In the FIRE-3 study, 592 patients were randomly assigned to FOLFIRI plus cetuximab or FOLFIRI plus bevacizumab. The study failed to show any improvement in investigator-assessed RR or PFS, but a statistically significant difference in OS was noted in favor of the cetuximab arm (28.7 v 25 months).38 A wider differential in OS was noted after limiting the analysis to the RAS-wt population (33.1 v 25.6 months). The investigators on this study attributed the discrepancy between PFS and OS to a differential in depth of response (DoR) in favor of the FOLFIRI-plus-cetuximab arm. Indeed, independent radiology review of FIRE-3 confirmed the superiority of the cetuximab arm in terms of RR, DoR, and early tumor shrinkage (Table 3).41 However, another explanation may lie in the limited number of patients (41%) exposed to anti-EGFR therapy after progression on the control arm.38 In line with the FIRE-3 clinical trial, the PEAK clinical trial suggested a survival advantage to anti-EGFR therapy versus bevacizumab in the first-line setting.39 In that study, 285 patients with KRAS-wt exon 2 were randomly assigned to receive FOLFOX plus panitumumab or FOLFOX plus bevacizumab. The primary end point of the © 2015 by American Society of Clinical Oncology


9

10

Study Acronym/Title

Study Design

Control Arm


Heinemann et al38; Stintzing et al41

FIRE-3/5-FU, Folinic Acid Randomized phase FOLFIRI ⫹ and Irinotecan III clinical trial in bevacizumab (FOLFIRI) Plus KRAS-wt exon Cetuximab Versus 2 mCRC; FOLFIRI Plus N ⫽ 592 Bevacizumab in First RAS-wt: Line Treatment n ⫽ 400 Colorectal Cancer (CRC)

Schwartzberg et al39 PEAK/Panitumumab Randomized phase FOLFOX ⫹ Efficacy in II clinical trial in bevacizumab Combination With KRAS-wt exon mFOLFOX6 Against 2 mCRC; N ⫽ Bevacizumab Plus 285 mFOLFOX6 in mCRC RAS-wt: Subjects With Wildn ⫽ 170 Type KRAS Tumors

Reference

Efficacy Objectives Primary Efficacy End Point


Key Toxicities


Primary: PFS; KRAS-wt: PFS: 10.9 months KRAS-wt: OS: 34.2 months Increased skin toxicity Anti-EGFR therapy was secondary: (panitumumab) v 10.1 (panitumumab) v 24.3 and given in 38% of the OS, RR months (bevacizumab); months (bevacizumab) hypomagnesemia bevacizumab arm v (HR, 0.87; P ⫽ .353) (HR, 0.62; P ⫽ .009) on the 21% of the RAS-wt: PFS: 13 months RR: 57.8% (panitumumab) panitumumab arm panitumumab arm (panitumumab) v 9.5 v 53.5% (bevacizumab) v increased months (bevacizumab); RAS-wt: OS: 41.3 months hypertension on (HR, 0.65; P ⫽ .029) (panitumumab) v 28.9 the bevacizumab months (bevacizumab) arm (HR, 0.63; P ⫽ .058) RR: 63.6% (panitumumab) v 60.5% (bevacizumab) FOLFIRI ⫹ cetuximab Primary: RR; Investigator review: KRAS-wt: OS: 28.7 months Increased skin toxicity 78% of patients on secondary: KRAS-wt: RR: 62% (cetuximab) v 25 and the cetuximab arm PFS, OS, (cetuximab) v 58% months (bevacizumab) hypomagnesemia received seconddepth of (bevacizumab) (OR, 1.18; (HR, 0.77; P ⫽ .017) on the cetuximab line treatment (48% response, P ⫽ .18) PFS: 10 months arm; increased of patients received early RAS-wt: RR: 65% (cetuximab) v 10.3 hypertension on bevacizumab-based treatment (cetuximab) v 60% months (bevacizumab) the bevacizumab treatment) shrinkage (bevacizumab) (OR, 1.28; (HR, 1.06; P ⫽ .55) arm 76% of the patients P ⫽ .128) RAS-wt: OS: 33.1 months on the bevacizumab Independent review: (cetuximab) v 25 arm received KRAS-wt: RR: 66.5% months (bevacizumab) second-line (cetuximab) v 55.6% (HR, 0.7; P ⫽ .0059) treatment (41% (bevacizumab) (OR, 1.58; PFS: 10.3 months received anti-EGFRP ⫽ .016) (cetuximab) v 10.2 based treatment) RAS-wt: RR: 72% months (bevacizumab) (cetuximab) v 56% (HR, 0.97; P ⫽ .77) (bevacizumab) (OR, 2; Depth of response: 48.2% P ⫽ .003) (cetuximab) v 33% (bevacizumab) (P ⬍ .001) Early treatment shrinkage: 67.5% (cetuximab) v 47.9% (bevacizumab) (P ⫽ .0013) (continued on following page)

FOLFOX ⫹ panitumumab

Experimental Arm(s)

Table 3. Anti-EGFR Versus Bevacizumab Plus Chemotherapy Studies in the First-Line Treatment of mCRC

Marwan G. Fakih



www.jco.org

CALGB 80405/Cetuximab and/or Bevacizumab Combined With Combination Chemotherapy in Treating Patients With Metastatic Colorectal Cancer

Study Acronym/Title

Control Arm

Randomized phase FOLFOX or FOLFIRI ⫹ III clinical trial; bevacizumab 1:1 randomization KRAS-wt exon 2: N ⫽ 1,137 RAS-wt: n ⫽ 526

Study Design FOLFOX or FOLFIRI ⫹ cetuximab

Experimental Arm(s)


Primary: OS; KRAS-wt: OS: 29.9 months secondary: (cetuximab) v 29 months PFS (bevacizumab) (HR, 0.92; P ⫽ .3) RAS-wt: OS: 30.8 months (cetuximab) v 30.3 months (bevacizumab) (HR, 0.9; P ⫽ .4)

Efficacy Objectives KRAS-wt: PFS: 10.4 months (cetuximab) v 10.8 months (bevacizumab) (HR, 1.04; P ⫽ .55) RR: 65.6% (cetuximab) v 57.2% (bevacizumab) (P ⫽ .002) RAS-wt: PFS: 10.9 months (cetuximab) v 11.4 months (bevacizumab) (HR, 1.1; P ⫽ .31) RR: 68.8% (cetuximab) v 56% (bevacizumab) (P ⬍ .001) FOLFOX-treated patients: HR, 0.86 for OS for cetuximab v bevacizumab (P ⫽ .2) FOLFIRI-treated patients: HR, 1.1 for OS for cetuximab v bevacizumab (P ⫽ .7)


Postprogression Treatment Increased skin toxicity Details not reported and diarrhea on the cetuximab arm and increased hypertension on the bevacizumab arm

Key Toxicities

Abbreviations: EGFR, epidermal growth factor receptor; FOLFIRI, fluorouracil, leucovorin, and irinotecan; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; mCRC, metastatic colorectal cancer; OR, odds ratio; OS, overall survival; PFS, progression-free survival; RR, response rate; wt, wild type.

Venook et al40, 43; Lenz et al42

Reference

Table 3. Anti-EGFR Versus Bevacizumab Plus Chemotherapy Studies in the First-Line Treatment of mCRC (continued)




11

Marwan G. Fakih

study was to estimate PFS. Although no significant difference in PFS was noted in the intent-to-treat population with KRAS-wt exon 2, a positive effect on PFS in favor of panitumumab emerged in the RAS-wt population (median PFS, 13 v 9.5 months). OS for the panitumumab arm was superior to that for the bevacizumab arm in the KRAS-wt intent-to-treat population (34.2 v 24.3 months) and approached significance in the RAS-wt population (41.3 v 28.9 months). The PEAK trial was limited by its phase II design, lack of a defined hypothesis, and a low rate of exposure to salvage anti-EGFR in the bevacizumab arm (38%). The CALGB 80405 study randomly assigned patients who had untreated mCRC to cetuximab or bevacizumab after the investigator’s choice of a FOLFOX or FOLFIRI backbone (Table 3). The study was powered to detect an improvement in OS of 5.5 months in favor of one of the treatment arms. Patients with KRAS-wt exon 2 tumors were randomly assigned to the bevacizumab (559 patients) or cetuximab (578 patients) arms. The majority of patients (73.4%) were treated with a FOLFOX backbone. No difference in PFS (bevacizumab, 10.8 months; cetuximab, 10.4 months) or OS was noted between the treatment arms (bevacizumab, 29 months; cetuximab, 29.9 months). Subgroup analysis did not support any benefit from bevacizumab or cetuximab in either the FOLFOX or FOLFIRI settings. A recent updated analysis confirmed a superior RR in the cetuximab arm in the KRAS-wt (65.6% v 57.2%) and RAS-wt population (68.8% v 56%).42 No advantages in terms of PFS or OS were noted for any of the biologicals in the RAS-wt population. A subset of patients (11%) underwent curative-intent resection of metastatic disease; an increased resectability rate was noted in the cetuximab arm.43 In this subgroup of patients, the median OS exceeded 5 years and was similar for patients on either the bevacizumab or cetuximab arm. In contrast to the FIRE-3 and PEAK trials, CALGB 80405 did not support the superiority of anti-EGFR therapy over bevacizumab in RAS-wt patients. Detailed analyses of the impact of postprogression therapy, tumor location, DoR, and other potential biomarkers of response such as BRAF and PIK3CA mutations have yet to be reported. The reason underlying the differential effect of first-line antiEGFR therapy between CALGB 80405 and FIRE-3 is unclear. However, one may hypothesize that the value of lifetime exposure to anti-EGFR therapy is superior to lifetime exposure to bevacizumab in mCRC. Such hypotheses are supported by the robust impact on OS when anti-EGFR agents are added to modern combination chemotherapy. This effect is in contrast to a modest impact of bevacizumab in similar settings. If this is the case, the sequence in which anti-EGFR therapy and bevacizumab are given may have little relevance as long as patients are exposed to anti-EGFR therapy in their treatment lifetime. The lack of difference in OS seen in CALGB 80405 may simply be related to higher exposure rates to anti-EGFR therapy postprogression in the control arm, as is typically the case for postprogression treatment rates in the United States.

Improving Patient Selection in CRC The best example of optimal patient selection is the progress in identifying suitable candidates for anti-EGFR therapy by excluding those with RAS-mut and BRAF-mut mCRC, which constitute approximately 55% of patients with mCRC (Fig 1). Therefore, one must consider the sensitivity of the RAS and BRAF mutation assay when selecting patients for anti-EGFR therapy. Sanger sequencing has poor sensitivity and requires a frequency of up to 20% mutant RAS to confirm the presence of a mutation. Other techniques such as pyrosequencing or quantitative polymerase chain reaction (PCR) can detect lower frequency RAS mutations (1% to 10%) and are commonly applied in the clinic. However, more robust technologies such as digital PCR are more sensitive and can detect RAS and BRAF mutations at mut:wt RAS DNA ratios as low as 0.01%. Such techniques can identify a greater percentage of patients with RAS mutations. Indeed, 16% of patients identified as having RAS-wt tumors by quantitative PCR were found to carry a low frequency of RAS mutations when evaluated by using the more sensitive digital PCR.48 However, tumors that had a mut:wt RAS DNA ratio less than 1% had RRs to anti-EGFR similar to those for RAS-wt tumors.48 A correlation between the mut:wt RAS DNA ratio and the likelihood of anti-EGFR clinical benefit was noted, with anti-EGFR therapy showing practically no benefit at mut:wt RAS DNA ratios exceeding 10%. Such reports stress the importance of developing standardized, sensitive RAS and BRAF assays and the need to identify and validate a threshold for RAS-mut sensitivity for clinical decision making. Several other candidate patient and tumor predictive markers of response are being investigated. Recent reports from the FIRE-3 clinical trial have suggested that anti-EGFR therapy has a decreased benefit in patients with right-colon tumors.49 In addition to having a higher rate of BRAF mutations, right-colon tumors are more likely have microsatellite instability (MSI) or to display a CpG island methylator phenotype, suggesting that such molecular characteristics and their effect on therapeutic outcome require further investigation. Indeed, a retrospective analysis recently reported shortened PFS for patients with CpG island methylator phenotype– high RAS-wt/ BRAF-wt tumors treated with anti-EGFR therapy.50 Other potential

RAS WT and BRAF WT RAS MT (KRAS exon 2) RAS MT (KRAS non-exon 2 and NRAS) BRAF MT

5% 11%

44%

40%

FUTURE DIRECTIONS IN MCRC

Further improvement in outcomes for mCRC will depend on better patient selection and on identifying and targeting mechanisms of drug resistance and targeting altered pathways in CRC. 12


Fig 1. RAS and BRAF distribution in patients with metastatic colorectal cancer (extrapolated from the PRIME study [The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy]). MT, mutation; WT, wild type. JOURNAL OF CLINICAL ONCOLOGY



biomarkers of anti-EGFR response in RAS-wt tumors include the EGFR ligands epiregulin (EREG), amphiregulin (AREG), and microRNA.51,52 Increased expression of EREG is associated with RAS-wt tumor status and improved prognosis.53 In addition to its potential prognostic value, an association between increased EREG expression and benefit from cetuximab in KRAS-wt tumors was reported in the COIN clinical trial, suggesting a potential predictive value for this marker in anti-EGFR treatment selection.54 MicroRNA tumor profiling identified increased mir-31 expression as a marker of resistance to cetuximab and poor outcome in RAS-wt fresh and paraffinembedded tumors.52 Similar findings were recently reported from the new EPOC (Eloxatin Peri-Operative Chemotherapy) trial.55 Other potential predictive markers of resistance to anti-EGFR include PIK3CA mutations, HER2 amplification, human epidermal growth factor receptor 3 (HER3) overexpression, and MET amplification, all of which require further validation.56,57 Targeting Mechanisms of Resistance Identifying mechanisms of innate or acquired resistance to approved agents in mCRC is essential for the design and development of novel combination therapies. One success in this area is the investigation of mechanisms of resistance to BRAF inhibitors in BRAF-mut CRC. The investigation of the BRAF inhibitor vemurafenib in BRAF-mut mCRC was associated with a disappointing RR of 5% and a median time to progression of less than 4 months.58 The unexpected resistance to BRAF inhibitors in BRAF-mut CRC

RAS WT and BRAF WT Excellent performance status RAS WT and BRAF WT Limited performance status or extremely elderly RAS MT Excellent performance status RAS MT Limited performance status or extremely elderly BRAF MT Excellent performance status BRAF MT Limited performance status or extremely elderly

is likely related to compensatory mechanisms that involve increased EGFR phosphorylation, KRAS activation, and downstream CRAF and ERK activation.59,60 This has led to ongoing clinical trials that investigate combinations of EGFR, BRAF, and MEK inhibitors with or without irinotecan. Indeed, preliminary clinical data from a study with cetuximab, vemurafenib, and irinotecan and another study with dabrafenib, trimatenib, and panitumumab have reported promising preliminary efficacy.61,62 SWOG1406 (Phase II Study of Irinotecan and Cetuximab With or Without Vemurafenib in BRAF Mutant Metastatic Colorectal Cancer) is currently comparing irinotecan plus cetuximab with irinotecan plus cetuximab and vemurafenib in patients with BRAF-mut CRCs who progressed after one to two prior lines of treatment. This study will provide more conclusive feedback on the impact of dual EGFR and BRAF targeting in BRAF-mut CRC. Several efforts are also ongoing to address anti-EGFR resistance in RAS and BRAF-wt tumors. One postulated mechanism of resistance to anti-EGFR therapy in these tumors has been the emergence of RAS and BRAF mutations during the course of cetuximab or panitumumab therapy. It was recently demonstrated that a majority of patients with RAS and BRAF-wt tumors will test positive for one or more KRAS, NRAS, or BRAF mutations in their cDNA or on repeat tumor biopsy before or at the time of anti-EGFR resistance.63 RAS mutations were detected in up to 60% of tumor samples biopsied at the time of resistance to anti-EGFR therapy, and these mutations were

FOLFOXIRIa ± bevacizumabb FOLFOX or XELOX or FOLFIRI ± bevacizumabb FOLFOX or FOLFIRI ± anti-EGFR therapyc

Capecitabine or fluorouracil/LV ± bevacizumabb FOLFOX or FOLFIRI ± anti-EGFR therapyc FOLFOX or FOLFIRI or XELOX ± bevacizumabb Consider dose modification for combination therapies (for example, fluorouracil bolus elimination)

FOLFOXIRIa ± bevacizumabb FOLFOX or XELOX or FOLFIRI ± bevacizumabb

Capecitabine or fluorouracil/LV ± bevacizumabb FOLFOX or FOLFIRI or XELOX ± bevacizumabb Consider dose modification for combination therapies (for example, fluorouracil bolus elimination)

Favor FOLFOXIRI ± bevacizumabb FOLFOX or FOLFIRI or XELOX ± bevacizumabb Early considerations for clinical trials Clinical benefit from anti-EGFR therapy is limited Capecitabine or fluorouracil/LV ± bevacizumabb FOLFOX or FOLFIRI or XELOX ± bevacizumabb Consider dose modification for combination therapies (for example, fluorouracil bolus elimination) Early considerations for clinical trials Clinical benefit from anti-EGFR therapy is limited

Fig 2. Treatment algorithm for first-line metastatic colorectal cancer on the basis of RAS/BRAF status. (a) FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) with or without bevacizumab is favored for downstaging for resection. (b) Bevacizumab should be avoided in patients with high risk of perforation or acute thrombotic events. (c) FOLFOX (infusional fluorouracil, leucovorin, and oxaliplatin) or FOLFIRI (fluorouracil, leucovorin, and irinotecan) with anti– endothelial growth factor receptor (EGFR) therapy is favored for downstaging to resection. (a, b, c) Patient and physician discussions regarding possible toxicities (alopecia, skin toxicity, neuropathy, acute thrombotic event risk, and perforation risk) should have a major influence on treatment selection. MT, mutation; WT, wild type. www.jco.org



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also readily detectable in patient sera before the development of antiEGFR resistance.64,65 Mathematical modeling indicates that the detected RAS mutations were present before anti-EGFR treatment and that their emergence in the tumor and cDNA was a result of clonal selection induced by anti-EGFR therapy.65 In a study of 24 patients who objectively responded to anti-EGFR therapy and subsequently progressed, 23 developed a detectable mutation involving the MAPK pathway; the majority of these mutations were RAS- or BRAF-activating mutations.63 Indeed, recent preclinical studies have demonstrated the reversal of acquired anti-EGFR resistance when MEK inhibition is added to therapy, which prompted the development of clinical trials investigating the combination of EGFR and MEK inhibitors in CRC.66 Molecular Heterogeneity in CRC and the Future of Drug Development The Cancer Genome Atlas Network recently reported on the comprehensive molecular characterization of 224 CRCs.67 Sixteen percent of these cases were hypermutated and occurred preferentially in the right colon. WNT pathway alterations were identified in 93% of all tumors and involved 16 different altered WNT pathway genes. Tumor growth factor ␤ signaling alterations were found preferentially in the hypermutated tumors (87%). In addition, ERBB family gene amplification or mutations were identified in 19% of tumors. In total, 24 genes were significantly mutated, many of which are considered targetable. This comprehensive molecular analysis points to several potential new targets in CRC and supports the design of novel clinical trials that address heterogeneity of colorectal tumors. For example, MSI-H tumors are hypermutated and are associated with lymphocytic infiltration and PD-1 and PD-L1 overexpression. Preliminary clinical data support response of these tumors to PD-1 targeting.67-69 This subgroup of patients can potentially benefit from immune targeted approaches. HER2 amplification occurs in approximately 3% of CRCs, appears to be more commonly associated with KRAS-wt tumors, and is associated with anti-EGFR resistance. These tumors respond to HER2 targeting in primary-derived xenograft models.70 ROS-1 and ALK-fusion rearrangements have been recently described in CRC, albeit at low frequencies (⬍ 1%), suggesting a role for ALK/ROS inhibitors in a small portion of patients with mCRC.71 c-MET amplification has also been reported in approximately 2% of CRCs and has been associated with a higher likelihood of metastatic disease, suggesting a potentially more aggressive REFERENCES 1. Siegel R, Ma J, Zou Z, et al: Cancer statistics, 2014. CA Cancer J Clin 64:9-29, 2014 2. de Gramont A, Figer A, Seymour M, et al: Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 18:2938-2947, 2000 3. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004 4. Cassidy J, Clarke S, Díaz-Rubio E, et al: Randomized phase III study of capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol 26:2006-2012, 2008 14


phenotype and a need to investigate the effectiveness of c-MET pathway inhibition in this subgroup.72 Because many of these recently recognized molecular drivers in mCRC are present at low frequency, a high level of collaboration among the National Cancer Institute, cooperative groups, and the pharmaceutical industry will be required to effectively study an array of targeted agents in an appropriately matched mCRC population. CONCLUSION

Significant progress has been made over the last two decades in the treatment of mCRC. OS has increased from approximately 12 months when treated with fluoropyrimidine monotherapy to nearly 30 months in recent clinical trials, especially in extended RAS-wt patients.44,73,74 More importantly, a better molecular understanding of CRC has allowed for better patient prognostication and for the launch of precision medicine in the treatment of mCRC. It is imperative that every patient with mCRC be evaluated for RAS (KRAS and NRAS) and BRAF status at the time of their diagnosis. The selection of optimal therapy should subsequently be based on the patient’s molecular phenotype but should also factor in the patient’s performance status, age, and goals of treatment (Fig 2). Future progress in treatment of CRC should focus on the development of novel therapeutics for RAS-mut cancers as well as other defined molecular subgroups such as BRAF, PIK3CA mutations, HER2 amplification, and patients with MSI. Additional efforts should seek to understand and overcome the various modes of resistance to anti-EGFR therapy in the patients with RAS-wt and BRAF-wt population.63,75 As systemic therapy improves, an increasingly responsive patient population has been converted from nonresectable to resectable status, with median OS exceeding 5 years in recent reports. Such encouraging outcomes support the conduct of additional studies that focus on improving resection rates in mCRC and identifying subgroups that benefit most from aggressive surgical interventions. AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the author are available with this article at www.jco.org.

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AUTHOR’S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Metastatic Colorectal Cancer: Current State and Future Directions The following represents disclosure information provided by author of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I ⫽ Immediate Family Member, Inst ⫽ My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or jco.ascopubs.org/site/ifc. Marwan G. Fakih Honoraria: Amgen, sanofi-aventis, Genentech, Sirtex Medical Consulting or Advisory Role: Amgen, sanofi-aventis, Sirtex Medical, Taiho Pharmaceutical

www.jco.org

Speakers’ Bureau: Amgen, Genentech, Bayer, sanofi-aventis, Sirtex Medical Research Funding: Novartis (Inst), Amgen (Inst)



Marwan G. Fakih

Acknowledgment The author acknowledges Nancy Linford and Keely Walker from the Office of Faculty and Institutional Support at City of Hope for their editorial assistance.




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